| Número de publicación||US8062739 B2|
|Tipo de publicación||Concesión|
| Número de solicitud||US 11/848,698|
| Fecha de publicación||22 Nov 2011|
| Fecha de presentación||31 Ago 2007|
| Fecha de prioridad||31 Ago 2007|
|También publicado como||CA2696798A1, EP2185210A2, US20090062408, WO2009032430A2, WO2009032430A3|
| Número de publicación||11848698, 848698, US 8062739 B2, US 8062739B2, US-B2-8062739, US8062739 B2, US8062739B2|
| Inventores||Kaifeng Liu, Brian Thomas, Steven Charlebois|
| Cesionario original||Zimmer, Inc.|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (103), Otras citas (88), Clasificaciones (12), Eventos legales (1) |
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
Hydrogels with gradient
US 8062739 B2
The present invention provides a hydrogel article having a multi-layered structure and exhibiting a gradient in polymer molecular weight. The invention also provides a method of forming a hydrogel article having a multi-layered structure and exhibiting a gradient in polymer molecular weight.
1. A hydrogel article comprising a multi-layered structure and having a first surface and an opposing second surface, wherein each layer of the multi-layered structure comprises a polymer having a different polymer molecular weight such that the multi-layered structure forms an increasing gradient in polymer molecular weight and strength from the first surface to the second surface, and wherein the gradient in polymer molecular weight results in a decreasing gradient in porosity and water concentration from the first surface to the second surface.
2. The hydrogel article of claim 1 wherein each layer of the multi-layered structure is formed from the same polymer but each layer of the multi-layered structure varies in polymer molecular weight.
3. The hydrogel article of claim 1 wherein the multi-layered structure exhibits a continuously increasing gradient of polymer molecular weight.
4. The hydrogel article of claim 1 wherein the multi-layered structure exhibits discrete layers of different polymer molecular weight.
5. A method of producing a hydrogel article having a multi-layered structure that exhibits a gradient in polymer molecular weight and comprises at least a first constituent and a second constituent, the method comprising
forming a first layer comprising the first constituent, wherein the first constituent is a polymer having a first molecular weight, and
contacting the first layer with the second constituent having a second molecular weight different than the first molecular weight, wherein the second constituent forms a second layer of the multi-layered structure, and whereby a hydrogel article is formed exhibiting a gradient of polymer molecular weight, and whereby the gradient of polymer molecular weight results in a gradient of strength, water concentration, and porosity.
6. The method of claim 5 wherein the first layer is either in a flowable state, a semi-solid state, or a solid state when the first layer is contacted with the second constituent.
7. The method of claim 5 wherein the second constituent is either in a flowable state, a semi-solid state, or a solid state when the first layer is contacted with the second constituent.
8. The method of claim 5 wherein the first layer is contacted by the second constituent by injection molding.
9. The method of claim 5 further comprising contacting the second or a subsequent layer of the multi-layered structure with a third or a subsequent constituent having a different polymer molecular weight such that a hydrogel article having a multi-layered structure exhibiting a gradient in polymer molecular weights is formed.
10. The method of claim 5 further comprising shaping and/or molding the hydrogel article.
11. The method of claim 5 wherein the resultant multi-layered structure of the hydrogel article exhibits discrete layers of polymer molecular weight, or a continuous gradient of polymer molecular weights, or a combination thereof.
12. The method of claim 5 wherein the hydrogel article is used as an articulating surface replacement having a first and a second surface, wherein the first surface is a bone-contacting surface and the second surface is an articulating surface, and wherein the gradient in polymer molecular weight ranges from a higher polymer molecular weight and strength at the bone-contacting surface to a lower polymer molecular weight and strength at the articulating surface, and wherein the higher polymer molecular weight results in lower water concentration and porosity at the bone-contacting surface and the lower polymer molecular weight results in higher water concentration and porosity at the articulating surface.
The present invention relates to hydrogel articles having a multi-layered structure and exhibiting a gradient in polymer molecular weight that may be suitable for use in biomedical or other applications.
Hydrogels are water-swellable or water-swollen materials whose structure is defined by a crosslinked network of hydrophilic homopolymers or copolymers. The hydrophilic homopolymers or copolymers can be water-soluble in free form, but in a hydrogel, they are rendered insoluble due to the presence of covalent, ionic, and/or physical crosslinks. In the case of physical crosslinking, the linkages can take the form of entanglements, crystallites, or hydrogen-bonded structures. The crosslinks in a hydrogel provide structure and physical integrity to the network.
One desirable feature of hydrogels for biomedical applications is that the hydrogels are very absorbent. Hydrogels can have a moisture content of upwards of 70% in many cases. In contrast, polyurethane hydrogels commonly employed in implantable devices are generally characterized by low moisture content, on the order of a few percent.
Hydrogels can attain a wide variety of mechanical properties. In general, hydrogels are observed to be pliable or rubbery, with a lubricious surface. Hydrogels are generally characterized by a low coefficient of friction owing to the water content and water-release properties at the surface. However, problems commonly associated with hydrogels that possess desirable absorbent properties include low mechanical strength and low shear strength. Devices made from PVA hydrogels have been observed to fail due to wear, such as by tearing, abrasion, or shredding. Thus, achieving improved mechanical strength and other physical properties for implantable articles made from hydrophilic polymers is desired.
SUMMARY OF THE INVENTION
The present invention provides a hydrogel article having a multi-layered structure and having a first and an opposing second surface. Each layer of the multi-layered structure is formed from a polymer having a different polymer molecular weight such that the multi-layered structure forms an increasing gradient in polymer molecular weight and strength from the first surface to the second surface. The gradient in polymer molecular weight also results in a decreasing gradient in porosity and water concentration from the first surface to the second surface.
The present invention also provides a method of producing a hydrogel article having a multi-layered structure that exhibits a gradient in polymer molecular weight and comprises at least a first constituent and a second constituent. The method comprises forming a first layer comprising the first constituent, which is a polymer having a first molecular weight. The first layer is then contacted with the second constituent, which is a polymer having a second molecular weight different than the first molecular weight, and forms a second layer of the multi-layered structure. The resulting hydrogel article exhibits a gradient of polymer molecular weight and the gradient of polymer molecular weight results in a gradient of strength, water concentration, and porosity.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows compressive stress-strain data for an injection molded PVA hydrogel in unconfined compression.
FIG. 2 shows compressive moduli of PVA hydrogels with different molecular weights.
FIG. 3 shows the behavior of creep strain over time during creep test for an injection molded PVA hydrogel.
FIG. 4 shows creep modulus over time for PVA hydrogels of different molecular weights.
The present invention provides for a hydrogel article comprising a multi-layered structure where each layer of the multi-layered structure comprises a polymer having a molecular weight such that the multi-layered structure forms a gradient in polymer molecular weight. In one embodiment, the layers of the multi-layered structure are formed from the same polymer but vary in polymer molecular weight. Furthermore, the gradient in polymer molecular weight results in a gradient in strength, porosity, and water concentration.
The hydrogel article also has a first and a second surface, the multi-layered structure defined therebetween with the first surface exhibiting a lower polymer molecular weight, a higher water concentration, a higher porosity, and a lower strength than the second surface. The hydrogel article of the present invention provides the combination of both a strong surface, which may be used as a bone-contacting surface, and a lubricious surface, which may be used as an articulating surface.
As used in this specification, the term “hydrogel” indicates that the article is able to absorb and retain water within a network of polymers, and does not imply that a change in volume of the article necessarily occurs upon hydration.
In one embodiment, the multi-layered structure of the hydrogel article exhibits a continuous gradient in polymer molecular weight. In another embodiment, the multi-layered structure of the hydrogel article exhibits discrete layers in polymer molecular weight. In another embodiment, the multi-layered structure of the hydrogel article exhibits a combination of continuous gradient and discrete layers in polymer molecular weight. Discrete layers represent an abrupt change in polymer molecular weight at the layer boundaries whereas a continuous gradient represents a gradual change in polymer molecular weight at the layer boundaries. In one embodiment, discrete layers can be represented as a substantially “stair-step” graph when plotted as a function of distance across the gradient versus polymer molecular weight whereas a continuous gradient would be represented as a substantially smooth line.
The present invention also provides a method of producing a hydrogel article having at least a first constituent and a second constituent and having a multi-layered structure that exhibits a gradient in polymer molecular weight. The method comprises forming a first layer of the multi-layered structure from the first constituent, which is a polymer having a first molecular weight. The first layer is then contacted with a second constituent, which is a polymer having a second molecular weight. The second constituent forms a second layer of the multi-layered structure of the hydrogel article. In one embodiment, the first and second constituents are the same polymer but vary in polymer molecular weight. Additional layers of the multi-layered structure can be formed by contacting the second layer with a third constituent having a third polymer molecular weight. The process of contacting the previously formed layer with a subsequent constituent having a different polymer molecular weight can be repeated as many times as desired. Although the inventive hydrogel article and method of making the hydrogel article is understood to describe a multi-layered structure having at least two layers, for clarity sake, the descriptions will be limited to the first and second layers. However, it should be understood that the descriptions of the first and second layers can be applied to any or all subsequent layers, e.g. layers three, four, five, etc. In one embodiment, the polymer molecular weight of the constituents, and thus the layers that are formed from the constituents, increases with each subsequent cycle of forming a layer and contacting the layer with a constituent. In another embodiment, the polymer molecular weight of the constituents, and thus the layers that are formed from the constituents, decreases with each subsequent cycle of forming a layer and contacting the layer with a constituent.
The result of the cycles of forming a layer and then contacting the layer with another constituent is a hydrogel article having a multi-layered structure exhibiting a gradient of polymer molecular weight. Polymer molecular weight is directly proportional to strength and inversely proportional to porosity and associated water concentration. The inverse relationship between polymer molecular weight and water concentration is believed to be a result of the increased molecular size and chain entanglement of the larger polymeric molecules. Additionally, increased polymer molecular weight also leads to higher resistance to creep, which is a time-dependent strain that occurs under the application of stress. Thus, a gradient in polymer molecular weight also results in a gradient in strength, porosity, and water concentration.
In one embodiment, the multi-layered structure is formed by contacting the first layer with a second constituent while the first layer is either in a flowable state, a semi-solid state, or a solid state. In one embodiment, the multi-layered structure is formed by contacting the first layer with a second constituent while the second constituent is either in a flowable state, a semi-solid state, or a solid state. The first layer is contacted with the second constituent by a variety of means including injection molding, solution casting, compression molding, extrusion, centrifugation, ultracentrifugation, or spin coating. In various embodiments, there is some degree of mixing of the first and second constituents at the boundary between the first and second layers. For instance, in embodiments where both the first layer, and therefore the first constituent, and the second constituent are in a flowable state, mixing between the two constituents may occur. Mixing between the first and second constituents results in a gradual change in polymer molecular weight comprising the polymer molecular weight gradient. Conversely, in embodiments where mixing between the first and second constituents does not occur, discrete layers of polymer molecular weight are created and thus, an abrupt change in polymer molecular weight comprising the polymer molecular weight gradient is created. For example, when the first layer and/or the second constituent are in a solid state, little to no mixing between the two constituents occurs. In some embodiments, the multi-layered structure of the hydrogel article contains a combination of discrete and gradual changes in polymer molecular weight at the layer boundaries. The boundaries are bounded by diffusion of molecular weights throughout the construct, but may be bound by other methods including reactive groups, gamma cross linking, cross linking agents, cyanoacrylates, or UV irradiation.
The inventive method also includes shaping and/or molding the hydrogel article comprising a polymer molecular weight gradient. In one embodiment, the hydrogel article formed by the inventive method is shaped and/or molded for use in an orthopedic procedure.
In one embodiment, the hydrogel article is an articulating surface replacement. In one embodiment, the articulating surface replacement has a first and a second surface and at least two layers forming the multi-layered structure. In one embodiment, the first surface of the articulating surface replacement is a bone-contacting surface and the second surface is an articulating surface and the gradient in polymer molecular weight ranges from a higher polymer molecular weight at the bone-contacting surface to a lower polymer molecular weight at the articulating surface. As described above, the higher polymer molecular weight results in lower water concentration and porosity and the lower polymer molecular weight results in higher water concentration and porosity. Additionally, the higher polymer molecular weight correlates with increased strength and the lower polymer molecular weight correlates with decreased strength. Thus, in an embodiment where the first surface of the articulating surface replacement is a bone-contacting surface and has a higher polymer molecular weight and the second surface is an articulating surface and has a lower polymer molecular weight, the first surface exhibits increased strength while the second surface exhibits increased water concentration. The increase in water concentration exhibited by the lower polymer molecular weight increases the lubricity of the material. In such an embodiment, the hydrogel article forming the articulating surface replacement provides desired strength at the bone-contacting surface and also desired lubricity at the articulating surface.
In one embodiment, the constituents that form the hydrogel article of the present invention are hydrophilic polymers. The hydrophilic polymers may be polyvinyl alcohol, for example, that vary in polymer molecular weight. By way of illustration only, other suitable hydrophilic polymers include polyhydroxyethyl methacrylate, polyvinyl pyrrolidone, polyacrylamide, polyacrylic acid, hydrolyzed polyacrylonitrile, polyethyleneimine, ethoxylated polyethyleneimine, polyallylamine, polyglycols as well as blends or mixtures of any of these hydrophilic polymers.
For example, in embodiments where the hydrophilic polymer is PVA, the constituents used to form the multi-layered structure may have polymer molecular weights selected from about 89 kilodaltons (kDa), about 130 kDa, about 186 kDa, and/or about 250 kDa. In certain embodiments, PVA molecular weights of about 89 kDa, about 130 kDa, about 186 kDa, and about 250 kDa corresponds to water contents of about 62.1%, 57.8%, 57.0%, and 56.1%, respectively.
In some embodiments of the present invention, the hydrophilic polymer may be a hydrogel blend including PVA and a second polymer having, for instance, hydrophobic recurring units and hydrophilic recurring units. For example, the second polymer of the hydrogel blend may be polyethylene-co-vinyl alcohol. As non-limiting examples, other suitable polymers include diol-terminated polyhexamethylene phthalate and polystyrene-co-allyl alcohol.
In certain embodiments of the invention, the hydrophilic polymer may be a copolymer. A copolymer derived from a hydrophobic monomer and a hydrophilic monomer may be suitable as the polymer, for example. One specific example of a suitable copolymer is polyethylene-co-vinyl alcohol, also known as “EVAL” “PEVAL” or “EVOH.” Other copolymers having hydrophilic recurring units and hydrophobic recurring units that may be suitable include poly(ethylene-co-acrylic acid) and polyethylene-co-methacrylic acid. Further examples of suitable materials to be used in the hydrogel article can be found in U.S. patent application Ser. No. 11/614,389, incorporated by reference herein in its entirety.
The hydrogel article may also include additional polymers, or conventional additives such as plasticizers, components for inhibiting or reducing crack formation or propagation, components for inhibiting or reducing creep, or particulates or other additives for imparting radiopacity to the article. By way of example only, an additive for imparting radiopacity can include metal oxides, metal phosphates, and/or metal sulfates such as barium sulfate, barium titanate, zirconium oxide, ytterbium fluoride, barium phosphate, and ytterbium oxide.
The hydrogel article of the present invention can be used in a variety of applications, including orthopedic procedures, as known in the field. By way of example, the hydrogel article can be used to provide artificial articular cartilage. The hydrogel article can also be employed as artificial meniscus or articular bearing components. For example, the hydrogel article having the combination of properties described above, e.g. a mechanically strong surface and a lubricious surface, may be used as an implant or in a reparative procedure of the knee joint, shoulder, etc. The hydrogel article can also be employed in temporomandibular, proximal interphalangeal, metacarpophalangeal, metatarsalphalanx, hip capsule or other joint repair. The hydrogel article of the present invention can also be used to replace or rehabilitate the nucleus pulposus of an intervertebral disc.
Optionally, a layer, more than one layer, or the hydrogel article of the present invention may be subjected to one or more crosslinking steps. Crosslinking may be carried out after forming a layer, after forming a multi-layered structure, after molding or shaping the hydrogel article, or at any other suitable point during processing. In one embodiment, a boundary between two layers may be subjected to crosslinking. In one embodiment, crosslinking of the boundary between two layers results in increased adhesion between the layers. A variety of conventional approaches may be used to crosslink the composite material, including, physical crosslinking (e.g., freeze thaw method), photoinitiation, irradiation and chemical crosslinking.
The following examples illustrate the synthesis of PVA polymer hydrogels to be used in the multi-layered structure in one embodiment of the invention. The resulting hydrogels were subjected to mechanical analysis.
PVA hydrogels were produced from four different PVA polymer molecular weights: 89 k, 130 k, 186 k and 250 k g/mol. The 89 k, 130 k, and 186 k polymers were purchased from Sigma Aldrich (St. Louis Mo.), and the 250 k PVA was purchased from Vam & Poval Co., Ltd. (Japan). A Haake POLYLAB rheometer was used to compound PVA and dimethyl sulfoxide (DMSO)/water. Disks having a diameter of 50 mm and a thickness of 4 mm were injection molded from the compounded PVA polymers. Molded samples were initially solvent exchanged in isopropyl alcohol for 24 hours, followed by sequential 24-hour solvent exchanges in deionized water. Samples remained in water for a minimum of 48 hours to fully hydrate prior to testing.
Unconfined compression testing was performed in deionized water at room temperature using an Instron 3345 test frame. Test samples consisted of fully hydrated 13 mm diameter, 4 mm thick cylinders that were punched out from the injection molded disks. Samples were loaded at 0.05 in/min according to ASTM D695 and tangent modulus was calculated at 10% strain increments up to 70% strain.
Static creep testing was performed in deionized water at room temperature on a custom-built test system. Cylindrical hydrogel samples with 13 mm diameter and 4 mm thickness punched from injection molded disks were loaded to a constant stress level of approximately 1 MPa for 16 hours, followed by 8 hours recovery. Change in thickness of the samples was recorded over time. Creep strain was calculated as the percent change from initial thickness. Creep modulus was defined as stress applied divided by the creep strain.
A TA Instruments 2980 TGA was used to verify water content of the hydrogels. In a nitrogen environment, samples were heated at 10° C. per minute to 110° C., and then held isothermal for 45 minutes to drive off water. The weight percent water loss was determined from the resulting TGA curve and corresponded to the water content of the gel.
A typical stress-strain data for an injection molded PVA hydrogel, e.g. 250 k g/mol PVA, is shown in FIG. 1. The stress-strain behavior is non-linear, with tangent modulus increasing rapidly with increasing strain level. Modulus was calculated by regression analysis of the compression data at percent strain of 20%, 30%, and 40% and is shown in FIG. 2. Asterisk indicated significant difference among the samples (p<0.05, statistical analysis by Design Expert). FIG. 2 shows a statistically significant trend for tangent modulus versus PVA molecular weight at 20% strain.
Hydrogels exhibited viscoelastic behavior under compressive creep load, as shown in FIG. 3. Test results showed that creep strain after 16 hours decreased with increasing PVA molecular weight. On unloading, all of the PVA hydrogels exhibited similar recovery trends, though final strain after 8 hours was lower for the higher molecular weight PVAs. FIG. 4 shows that creep modulus also showed a strong correlation with the molecular weight of PVA in the sample.
Because the process of molding the hydrogels utilizes dimethylsulfoxide as the solvent, the final water content of the hydrogels after solvent exchange is different than the solvent concentration at time of molding. Water concentration is determined as the percentage weight loss using a thermogravametric analysis instrument with a ramp of 10° C./min to 120° C., an isotherm for 45 minutes, followed by a 10° C./min ramp to 160° C. The final water content measured from fully hydrated, injection molded PVA components differed from the initial 54% solvent concentration for each molecular weight PVA at the compounding step (Table 1).
|Water content of hydrogels.
||Molecular weight (k g/mol)
Results from the static unconfined compression and compressive creep experiments demonstrate that bulk polymer molecular weight affects the mechanical properties of injection molded PVA hydrogels.
The invention is further set forth in the claims listed below. This invention may take on various modifications and alterations without departing from the scope thereof. In describing embodiments of the invention, specific terminology is used for the sake of clarity. The invention, however, is not intended to be limited to the specific terms so selected, and it is to be understood that each term so selected includes all technical equivalents that operate similarly.
| Patente citada|| Fecha de presentación|| Fecha de publicación|| Solicitante|| Título|
|US3200178||7 Dic 1961||10 Ago 1965||Kurashiki Rayon Co||Polyvinyl alcohol spinning solutions and fibers produced therefrom|
|US3862265||3 Abr 1972||21 Ene 1975||Exxon Research Engineering Co||Polymers with improved properties and process therefor|
|US3875302||7 Ago 1973||1 Abr 1975||Kuraray Co||Gelled vinyl alcohol polymers and articles therefrom|
|US4036788||11 Feb 1975||19 Jul 1977||Plastomedical Sciences, Inc.||Anionic hydrogels based on heterocyclic N-vinyl monomers|
|US4058491||11 Feb 1975||15 Nov 1977||Plastomedical Sciences, Inc.||Cationic hydrogels based on heterocyclic N-vinyl monomers|
|US4060678||11 Feb 1975||29 Nov 1977||Plastomedical Sciences, Inc.||Cationic hydrogels based on hydroxyalkyl acrylates and methacrylates|
|US4071508||11 Feb 1975||31 Ene 1978||Plastomedical Sciences, Inc.||Anionic hydrogels based on hydroxyalkyl acrylates and methacrylates|
|US4279795||28 Dic 1973||21 Jul 1981||Kuraray Co., Ltd.||Anticoagulants|
|US4300820||27 Oct 1980||17 Nov 1981||The Kendall Company||Containing a vinyl amide mono or copolymer and an addition copolymer|
|US4379874||7 Jul 1980||12 Abr 1983||Stoy Vladimir A||Polymer composition comprising polyacrylonitrile polymer and multi-block copolymer|
|US4451599||19 Abr 1982||29 May 1984||American Can Company||Ethylene-vinyl alcohol copolymer|
|US4451630||16 Jun 1983||29 May 1984||Atkinson Ivor B||N-vinyl pyrrolidone, (meth-)acrylic acid, and hydroxyalkyl (meth-)acrylate, with 1,3,5-tris(propenoxy)-2,4,6-triazine, or perhydro-2,4,6-triketo-1,3,5-tris(propen-2)-1,3,5-triazine as crosslinking agent|
|US4464438||2 May 1983||7 Ago 1984||Mobil Oil Corporation||Polyamide, polyurethane or polyoxazoline processing aid|
|US4472542||8 Ago 1983||18 Sep 1984||Nippon Oil Co., Ltd.||Freeze-dried polyvinyl alcohol gel|
|US4521568 *||1 Jun 1982||4 Jun 1985||Asahi Kasei Kogyo Kabushiki Kaisha||Sequentially produced multilayer acrylic resin composition|
|US4640941||7 Ene 1986||3 Feb 1987||Alcon Laboratories||Hydrogels containing siloxane comonomers|
|US4656216||19 Mar 1985||7 Abr 1987||Mueller Albrecht||Thermoplastically processable polyvinyl alcohol compositions, process for their preparation, and films and moldings prepared from them|
|US4663358||25 Abr 1986||5 May 1987||Biomaterials Universe, Inc.||Porous and transparent poly(vinyl alcohol) gel and method of manufacturing the same|
|US4664857||27 Jun 1985||12 May 1987||Nippon Oil Company, Limited||Process for preparing a hydrogel|
|US4699146||12 Sep 1985||13 Oct 1987||Valleylab, Inc.||Radiation cross-linked polymer with three-dimensional matrix, plasticizer|
|US4734097||28 Mar 1985||29 Mar 1988||Nippon Oil Company, Ltd.||Freezing anticoagulants|
|US4771089||10 Jul 1985||13 Sep 1988||Minnesota Mining And Manufacturing Co.||Polymer blends with high water absorption|
|US4772287||20 Ago 1987||20 Sep 1988||Cedar Surgical, Inc.||Prosthetic disc and method of implanting|
|US4808353||8 Ene 1986||28 Feb 1989||Nippon Oil Co., Ltd.||Process for preparing an artificial biological membrane|
|US4842597||15 May 1987||27 Jun 1989||Fulmer Yarsley Ltd.||Non-crosslinked hydrogel of hydrophobic acrylates and hydrophilic vinyl amides or hydroxy alkyl acrylates|
|US4851168||28 Dic 1988||25 Jul 1989||Dow Corning Corporation||Novel polyvinyl alcohol compositions and products prepared therefrom|
|US4859719||13 Jun 1988||22 Ago 1989||Minnesota Mining And Manufacturing Company||Polymer blends with high water absorption|
|US4871490||30 Dic 1987||3 Oct 1989||Politechnika Lodzka, Lodz, Ul. Zwirki||Method of manufacturing hydrogel dressings|
|US4874562||9 Feb 1987||17 Oct 1989||Biomaterials Universe, Inc.||Method of molding a polyvinyl alcohol contact lens|
|US4875562||28 Ene 1988||24 Oct 1989||Kabushiki Kaisha Daikin Seisakusho||Lock-up damper for torque converter|
|US4915974||17 Feb 1989||10 Abr 1990||Nabisco Brands, Inc.||Polyvinyl alcohol esterified with fatty acids; foods|
|US4956122||23 Dic 1988||11 Sep 1990||Uniroyal Chemical Company, Inc.||Lubricating composition|
|US4966924||15 May 1989||30 Oct 1990||Biomaterials Universe, Inc.||Soft contact lens and method of manufacturing the same|
|US4988761||26 Abr 1989||29 Ene 1991||Dow Corning K.K.||Polyvinyl alcohol hydrogel formed by gelation, heat treatment, useful for providing improved cartilage in humans|
|US5028648||12 Jul 1990||2 Jul 1991||Air Products And Chemicals, Inc.||Extrudable polyvinyl alcohol compositions containing thermoplastic polyurethane|
|US5047055||21 Dic 1990||10 Sep 1991||Pfizer Hospital Products Group, Inc.||Prosthetics; biocompatibility; compressive strength|
|US5053455||20 Feb 1991||1 Oct 1991||Hoechst Ag||Graft polymers, containing polyvinyl acetal groups, on polyurethane grafting substrates, processes for the preparation thereof, and the use therefor|
|US5106876||20 Sep 1989||21 Abr 1992||Terumo Kabushiki Kaisha||Water-insoluble hydrogel and method for production thereof by using radiation, freezing and thawing|
|US5118779||10 Oct 1989||2 Jun 1992||Polymedica Industries, Inc.||Hydrophilic polyurethane elastomers|
|US5122565||26 Oct 1990||16 Jun 1992||Shell Oil Company||Stabilized polyketone polymers containing a mixture of a hydroxyapatite and an alumina hydrogel|
|US5157093||9 May 1991||20 Oct 1992||Ciba-Geigy Corporation||Hydroxyethyl cellulose derivatives containing pendant (meth)acryloyl units bound through urethane groups and hydrogel contact lenses made therefrom|
|US5189097||22 Oct 1991||23 Feb 1993||Rohm And Haas Company||Polymeric blends|
|US5192326||9 Sep 1991||9 Mar 1993||Pfizer Hospital Products Group, Inc.||Prosthetic nucleus for implanting disks, hydrogel beads and semipermeable cover|
|US5244799||17 Dic 1991||14 Sep 1993||Anderson David M||Mixing to viscous isotropic phase hydrophilic monomer, water, ionic surfactant and polymerizing agent; equilibrating to cubic phase; polymerizing in cubic phase; water bath with polymer and nonionic surfactant; ionic surfactant diffusing|
|US5276079||15 Nov 1991||4 Ene 1994||Minnesota Mining And Manufacturing Company||Pressure-sensitive poly(n-vinyl lactam) adhesive composition and method for producing and using same|
|US5288503||16 Jun 1992||22 Feb 1994||Srchem Incorporated||Water-permeable diffusion barrier of polyvinyl alcohol|
|US5306311||17 Dic 1991||26 Abr 1994||Regen Corporation||Prosthetic articular cartilage|
|US5311223||7 Jun 1993||10 May 1994||Johnson & Johnson Vision Products, Inc.||Hydroxyethyl methacrylamide and hydroxyoctyl methacrylate monomers; soft hydrogel contact lenses|
|US5315478||16 Oct 1991||24 May 1994||Fujitsu Personal Systems, Inc.||Memory card tray for portable computer|
|US5334634||13 Ago 1991||2 Ago 1994||Novamont S.P.A.||Polymer compositions for the production of articles of biodegradable plastics material and methods for their preparation|
|US5336551||14 Dic 1992||9 Ago 1994||Mizu Systems, Inc.||Reinforced polyvinyl alcohol hydrogels containing uniformly dispersed crystalline fibrils and method for preparing same|
|US5358525||28 Dic 1992||25 Oct 1994||Fox John E||Bearing surface for prosthesis and replacement of meniscal cartilage|
|US5360830||18 Feb 1994||1 Nov 1994||Novamont S.P.A.||Closed-pore, acrylic acid-ethylene copolymer or ethylene-vinyl alcohol copolymer and a starch|
|US5362803||16 Jul 1993||8 Nov 1994||Rohm And Haas Company||Polymeric blends of polyvinyl alcohol copolymers with copolymers of unsaturated monomers|
|US5364547||26 Abr 1993||15 Nov 1994||The Dow Chemical Company||Lubricants containing perfluorocyclobutane rings|
|US5407055||16 Nov 1993||18 Abr 1995||Kao Corporation||Conveyor apparatus and method having flexible goods receptacle members|
|US5409966||15 Oct 1993||25 Abr 1995||Minnesota Mining And Manufacturing Company||Method for producing pressure sensitive poly (N-vinyl lactam)|
|US5410016||1 Mar 1993||25 Abr 1995||Board Of Regents, The University Of Texas System||A curable additional polymerizable macromolecular monomers comprising at least one water soluble region, at least one degradable, hydrolyzable region and free radical polymerizable end groups; drug delivery|
|US5458643||1 Feb 1994||17 Oct 1995||Kyocera Corporation||Artificial intervertebral disc|
|US5527271||30 Mar 1994||18 Jun 1996||Bristol-Myers Squibb Co.||Thermoplastic hydrogel impregnated composite material|
|US5540033||10 Ene 1994||30 Jul 1996||Cambrex Hydrogels||Integrated Manufacturing process for hydrogels|
|US5552096||31 May 1995||3 Sep 1996||Exxon Chemical Patents Inc.||Multiple reaction process in melt processing equipment|
|US5576072||1 Feb 1995||19 Nov 1996||Schneider (Usa), Inc.||Coating on plastic substrates for medical devices such as catheters, catheter balloons and stents|
|US5580938||22 Oct 1991||3 Dic 1996||Hoechst Aktiengesellschaft||Graft polyvinyl acetals having acetal groups from etherified ω-hydroxy(poly)alkoxyalkanals, processes for their preparation and their use|
|US5624463||25 Abr 1994||29 Abr 1997||Regen Biologics, Inc.||Prosthetic articular cartilage|
|US5632774||14 May 1996||27 May 1997||Babian; Hamik||In-the-shell hydration to make implant filler material and prosthesis employing same|
|US5674295||26 Abr 1996||7 Oct 1997||Raymedica, Inc.||Prosthetic spinal disc nucleus|
|US5681300||27 Nov 1995||28 Oct 1997||The Procter & Gamble Company||Absorbent article having blended absorbent core|
|US5705296||7 Jun 1995||6 Ene 1998||Mitsubishi Cable Industries, Ltd.||Lithium phosphates with cobalt oxide as electrolytes|
|US5709854||30 Abr 1993||20 Ene 1998||Massachusetts Institute Of Technology||Tissue formation by injecting a cell-polymeric solution that gels in vivo|
|US5711960||24 May 1995||27 Ene 1998||Takiron Co., Ltd.||Biocompatible implant material comprising a tri-axial or more three-dimensional fabric|
|US5716404||16 Dic 1994||10 Feb 1998||Massachusetts Institute Of Technology||Breast tissue engineering|
|US5723311||2 Jun 1995||3 Mar 1998||Human Genome Sciences, Inc.||Human DNA topoisomerase I α|
|US5723331||6 Jun 1995||3 Mar 1998||Genzyme Corporation||Methods and compositions for the repair of articular cartilage defects in mammals|
|US5834029||20 Jul 1994||10 Nov 1998||Cytotherapeutics, Inc.||Nerve guidance channel containing bioartificial three-dimensional hydrogel extracellular matrix derivatized with cell adhesive peptide fragment|
|US5879713||23 Ene 1997||9 Mar 1999||Focal, Inc.||Targeted delivery via biodegradable polymers|
|US5891826||26 Nov 1997||6 Abr 1999||Eastman Kodak Company||Heat activated adhesive on release paper, peeling, imaging, lamination and removal from support|
|US5941909||7 Ago 1997||24 Ago 1999||Mentor Corporation||Comprising flexible elastomeric hollow shell and filling material comprising high molecular weight polyacrylamide polymer; biocompatible, having good aesthetics; used for breast implants, testicular prosthesis, tissue expansion|
|US5976186||25 Jun 1996||2 Nov 1999||Stryker Technologies Corporation||Hydrogel intervertebral disc nucleus|
|US5981826||17 Sep 1997||9 Nov 1999||Georgia Tech Research Corporation||Poly(vinyl alcohol) cryogel|
|US6001395 *||15 Jul 1996||14 Dic 1999||Danbiosyst Uk Limited||Polymeric lamellar substrate particles for drug delivery|
|US6015576||29 Ago 1997||18 Ene 2000||Bio-Sphere Technology, Inc.||Method for inducing a systemic immune response to an antigen|
|US6017577||1 Feb 1995||25 Ene 2000||Schneider (Usa) Inc.||Non-toxic and biocompatible; ideally suited for use on medical devices, particularly catheters, catheter balloons and stents; low coefficients of friction|
|US6040493||24 Abr 1998||21 Mar 2000||Replication Medical, Inc.||An interconnected transport layer and reservoir in osmotic equilibrium of aqueous solutions; impervious to infectious aagents; permeable to body fluids and water soluble compounds; cell cultures; cell proliferation; drug delivery|
|US6080488||24 Mar 1998||27 Jun 2000||Schneider (Usa) Inc.||A coating of lubricant polyureaurethane copolymers for metals|
|US6117449||14 Ene 1998||12 Sep 2000||Bio-Sphere Technology, Inc.||A liposomal preparation comprising lyophilized liposomes containing at least one antigen selected from the group consisting of hepatitis b and hepatitis c antigens and mixtures, and liposomes have atleast three different sizes|
|US6120904||24 May 1999||19 Sep 2000||Schneider (Usa) Inc.||Polymer substrate coated with an interpenetrating network of two different hydrogels, one is a polyureaurethane hydrogel polymer which is linked to the ammonia plasma-treated substrate by covalent urea linkages; slippery; catheters|
|US6121341||22 Mar 1996||19 Sep 2000||Board Of Regents, The University Of Texas System||Redox and photoinitiator systems for priming and improved adherence of gels to substrates|
|US6129761||7 Jun 1995||10 Oct 2000||Reprogenesis, Inc.||Mixing dissociated cells with solution comprising biocompatible hyaluronic acid, alginate polymer capable of crosslinking to form hydrogel, forming suspension, implanting into animal, crosslinking to form hydrogel matrix|
|US6132468||10 Sep 1998||17 Oct 2000||Mansmann; Kevin A.||Arthroscopic replacement of cartilage using flexible inflatable envelopes|
|US6139963||20 Nov 1997||31 Oct 2000||Kuraray Co., Ltd.||Polyvinyl alcohol hydrogel and process for producing the same|
|US6146686||23 Abr 1999||14 Nov 2000||Isotis B.V.||Subjecting non-porous material to mechanical or chemical surface treatment until surface roughness with average peak distance between 10 and 1,000 nm is obtained; roughened surface can be subjected to precipitation of calcium phosphate|
|US6156345||21 Dic 1999||5 Dic 2000||Surmodics, Inc.||Crosslinkable macromers bearing initiator groups|
|US6156572||25 Sep 1998||5 Dic 2000||Neurotech S.A.||Three dimensional high water content matrix having at least one cellular adhesion molecule covalently immobilized and homogeneously dispersed; facilitates tissue regeneration or replacement|
|US6162456||24 Sep 1992||19 Dic 2000||Ortho-Mcneil Pharmaceutical, Inc.||Adhesive transdermal drug delivery matrix of a physical blend of hydrophilic and hydrophobic polymers|
|US6180132||17 Sep 1998||30 Ene 2001||Sherwood Services, Ag||Hydrogel wound dressing and the method of making and using the same|
|US6180606||13 Ene 1998||30 Ene 2001||Gensci Orthobiologics, Inc.||Compositions with enhanced osteogenic potential, methods for making the same and uses thereof|
|US6184197||10 Sep 1997||6 Feb 2001||The Procter & Gamble Company||Laundry detergent comprising a polyvinylpyrrolidone or polyvinylimidazole polymer whose nitrogen atom(s) are linked to an active alcohol ester group of given formula, surfactant, carriers, and adjuvants; delayed release perfume|
|US6187048||23 May 1995||13 Feb 2001||Surgical Dynamics, Inc.||Comprising a conformable material adapted to fill cavities within the disc and to partially polymerize in-situ to form a shaped, resiliently deformable prosthesis of polyhydroxy-alkylmethacrylates and/or polyalkylmethacrylates|
|US6207185||10 Oct 1997||27 Mar 2001||Bio-Sphere Technology||Method for inducing a systemic immune response to an HIV antigen|
|US6211296||29 Oct 1999||3 Abr 2001||The B. F. Goodrich Company||Hydrogels containing substances|
|US20030104031 *||25 Nov 2002||5 Jun 2003||Francis Dumont||Controlled release polymeric compositions of bone growth promoting compounds|
|US20040002770 *||2 Jun 2003||1 Ene 2004||King Richard S.||Polymer-bioceramic composite for orthopaedic applications and method of manufacture thereof|
|1||"Lecture 7: Hydrogel Biomaterials: Structure and Physical Chemistry," Spring 2003, 8 pages.|
|2||Anseth et al. "In situ forming degradable networks and their application in tissue engineering and drug delivery." J. Controlled Release 78 (2002), 199-209, 2002.|
|3||Bass L.S. "Laser Tissue Welding: A Comprehensive Review of Current and Future Clinical Applications," Lasers in Surgery and Medicine, 1995, pp. 315-349. vol. 17.|
|4||Bray, J.C. et al. "Poly(vinyl Alcohol) Hydrogels for Synthetic Articular Cartilage Material," Biomed. Mater. Res., vol. 7, pp. 431-443, 1973.|
|5||Bray, J.C. et al. "Poly(vinyl Alcohool) Hydrogels: Formation by Eelctron Beam Irradiation of Aqueous Solutions and Subsequent Crystallization." J. Applied Polymer Sci., vol. 17, pp. 3779-3794, 1973.|
|6||Bryant, S.J. et al. "Crosslinking Density Influences Chrondrocyte Metabolism in Dynamically Leaded Photocrosslinked Poly(ethylene glycol) Hydrogels." Ann. Biomed. Eng., Mar. 2004, pp. 407-417, vol. 3, No. 3.|
|7||Bryant, S.J. et al. "Photocrosslinkable Poly(ethylene oxide) and Poly (vinyl alcohol) Hydrogels for Tissue Engineering Cartilage." 21st Annual Conference and the 1999 Annual Fall Meeting of the Biomedical Engineering Society, Oct. 13-15, 1999, Atlanta, GA; Engineering in Medicine and Biology 1999, p. 751, vol. 2.|
|8||Bryant, S.J. et al. "The Effects if Scaffold thickness on Tissue Engineered Cartilage in Photocrosslinked Poly (ethylene oxide) hydrogels." Biomaterials 22, 2001, pp. 619-628.|
|9||Bryant, Stephanie et al, "Phtocrosslinkable Poly(ethylene oxide) and Poly (vinyl Alcohol) Hydrogels for Tissue Engineering Cartilage", First Joint BMES/EMBS Conference, p. 751, Oct. 1999 Atlanta Georgia.|
|10||Carey et al., Adv. Org. Chem., Part B., p. 892, 2001.|
|11||Chow et al.,"Octacalcium Phosphate," Monograph in Oral Science, vol. 18, pp. 94-112 and 130-148.|
|12||Covert, R.J. et al. "Friction and Wear Testing of a New Biomaterial for Use as an Articular Cartilage Substitute," BED 50 (2001), 355-356, Bioengineering Conference, ASME 2001.|
|13||D. A. Babb et al., Perfluorocyclobutane Aromatic Ether Polymers. III. Synthesis and Thermal Stability of a Thermoset Polymer Containing Triphenylphosphine Oxide; Journal of Applied Polymer Science, vol. 69, 2005-2012 (1998), John Wiley & Sons, Inc.|
|14||Ding, Mei Yee. Characterisation of Polyvinyl Alcohol Hydrogels, 2003. Undergraduate Chemical Engineering Thesis, University of Queensland, Brisbane QLD 4072, Australia.|
|15||Durmaz, S. et al. "Phase Separation during the Formation of Poly(acrylamide) Hydrogels" Polymer 41, 2000, pp. 5729-5735.|
|16||EP Search Report for EP 06256525.4 dated May 20, 2007.|
|17||EP Search Report for EP Application No. 050010009.9-2115 dated Mar. 1, 2005.|
|18||EP Search Report for EP06255568.5, Jun. 15, 2007.|
|19||EP Search Report for EP06256452.1 dated May 23, 2007.|
|20||EPO Invitation to Pay additional fees and Annex to Search Report for PCT/US2006/046725 dated Apr. 22, 2008, 8 pages.|
|21||Gong, J.P. et al. "Friction of Polymer Gels and the Potential Application as Artificial Cartilage." SPIE, Mar. 1999, pp. 218-225, vol. 3669.|
|22||Green et al. Organic Chemistry Principles and Industrial Practice. Wiley VCH, 2003.|
|23||Guilherme, R. et al. "Hydrogels based on PAAm network with PNIPAAm included: hydrophilic-hydrophobic transition measured by the partition of Organe II and Methylene Blue in Water." Polymer 44, 2003, pp. 4213-4219.|
|24||Haralabakopoulus et al. J. Appl. Poly. Sci., 69, 1885-1890 (1998).|
|25||Hassan C.M. "Diffusional Characteristics of Freeze/Thawed Poly(vinyl alcohol) hydrogels: Applications to protein controlled release from multilaminate devices." Eur. J. Pharm. and Biopharm., 2000, pp. 161-165, vol. 49.|
|26||Hassan et al. "Cellular PVA Hydrogels Produced by Freeze/Thawing." J. Appl. Poly. Sci. 76, 2075 (2000).|
|27||Hassan et al., Structure and Applications of Poly(vinyl Alcohol) Hydrogels Produced by Conventional Crosslinking or by Freezing/Thawing Methods; Advances in Polymer Science, vol. 153, 37-65 (2000), Springer-Verlag Berlin Heidelberg.|
|28||Hassan, C.M. et al. "Modeling of Crystal Dissolution of Poly(vinyl alcohol) gels produced by freezing/thawing processes." Polymer 41, 2000, pp. 6729-6739.|
|29||Hassan, C.M. et al. "Structure and Morphology of Freeze/Thawed PVA Hydrogels," Macromolecules, 2000, pp. 2472-2479, vol. 33, No. 7.|
|30||Hickey et al. :Solute Diffusion in Poly(vinyl)alchohol/poly(acrylic acid) composite membranes prepared by freezing/thawing techniques. Polymer 38, pp. 5931-5936 (1997).|
|31||Hickey et al., "Mesh Size and Diffusive Characteristics of Semicrystalline . . . ", Journal of Membrane Science 107 (1995) pp. 229-237.|
|32||Hickey, A.S. et al. "Solute Diffusion in Poly(vinyl) alcohol/poly(acrylic) acid composite membranes prepared by freezing/thawing techniques." J. Memb. Sci. 107, 1995, pp. 229-237.|
|33||International Union of Pure and Applied Chemistry (IUPAC), Glossary of Basic Terms in Polymer Science; Pure Appl. Chem. 68, 2287-2311 (1996), Great Britain.|
|34||ISR/WO for PCT/EP2005/010931 dated Feb. 16, 2006.|
|35||ISR/WO for PCT/US2006/006356 dated Jun. 22, 2006, 9 pages.|
|36||ISR/WO for PCT/US2006/046725 dated Jul. 28, 2008.|
|37||ISR/WO for PCT/US2007/064782 dated May 3, 2008.|
|38||Jaguar-Grodzinski, J. "Biomedical Application of Functional Polymers." Reactive and Functional Polymers 39 (1999) 99-138.|
|39||Jagur-Grodzinski in Reactive and Functional Polymers, 39, 99-139 (1999).|
|40||Kawanishi, K. Thermodynamic Consideration of the Sol-Gel Transition in Polymer Solutions. 35th Annual Meeting of the Society of Polymer Science, Japan 1986.|
|41||Kobayashi, M. et al. "Development of an Artificial Meniscus Using Polyvinyl alcohol-hydrogel for early return to, and continuance of, athletic life in sportspersons with severe meniscus injury." Abstract only, The Knee 10, 2003, p. 53.|
|42||Kobayashi, M. et al. "Preliminary Study of Polyvinylalcohol-hydrogel (PVA-H) artificial meniscus." Biomaterials 24, 2003, pp. 639-647.|
|43||LeGeros R. Z., "Calcium phosphates in oral biology and medicine," Monograph in Oral Science, vol. 15, pp. 1-201.|
|44||Lester, C.L. et al. "Physical Properties of Hydrogels Synthesized from Lyotropic Liquid Crystalline Templates" Chem. Mater. 15, 2003, pp. 3376-3384.|
|45||Li et al. Anal. Biochem., 256, 130-132 (1998).|
|46||Lin-Gibson et al. "Synthesis and Characterization of PEG Dimethacrylates and Their Hydrogels." Biomacromolecules 2004, 5, 1280-1287, 2004.|
|47||Lozinsky, V. I. and Damshkaln, L. G. Study of cryostructuration of polymer systems. XVIII. Poly(vinyl alcohol) cryogels: Dynamics of cryotropic gel formation. Journal of Applied Polymer Science 2000 77:2017-2023.|
|48||Lozinsky, V.I. "On the Possibility of Mechanodestruction of Poly (vinyl Alcohol) Molecules under Moderate Freezing of its Concentrated Water Solutions." Polymer Bulletin, 15, p. 333-340 (1986).|
|49||Lozinsky, V.I. et al. "Study of Cryostructuration of Polymer Systems, XVII. Poly(vinyl alcohol) Cryogels: Dynamics of the Cryotropic Gel Formation." J. Appl. Polymer Sci., vol. 77, 2017-2023 (2000).|
|50||Lozinsky, V.I. et al. "Study of Cryostructures of Polymer Systems, XIV. Poly(vinyl alchohol) Cryogels: Apparent Yield of Freeze-Thaw Induced Gelation of Concentrated Aqueous Solutions of the Polymer." J. Applied Polymer Sci., vol. 77, 1822,1831 (2000).|
|51||Lozinsky, V.I. et al. "Swelling Behavior of poly (vinyl alcohol) cryogels employed as matrices for cell immobilization." Enzyme Microb. Technol., vol. 18.|
|52||Lu et al. Journal of Controlled Release, 57, 291-300 (1999).|
|53||Mano, V. et al. "Blends Composed of Poly(N-Isopropylacrylamide) and an Ethylene/Vinyl Alcohol Copolymer: Thermal and Morphological Studies" J. App. Polymer Sci., 2004, pp. 501-505.|
|54||Mondino et al. Rad. Chem. and Phys. 55, 723-726 (1999).|
|55||Mondino, A.V. et al. "Physical properties of gamma irradiated poly (vinyl alcohol) hydrogel preparations" Radiation Physics and chemistry, 55, p. 723,726 (1999).|
|56||Moro et. al. "Surface Grafting of Artificial Joints with Biocompatible Polymer for Preventing Periprosthetic Osteolysis." Nature Materials, 3, 829 (2004).|
|57||Oka M et al. "Development of artificial articular cartilage," Pro. Inst. Mech. Eng. 2000 214:59-68.|
|58||Park K.R. et al. "Synthesis of PVA/PVP Hydrogels having Two-Layer by Radiation and their Physical Properties." Rad. Phys. and Chem., Jun. 2003, pp. 361-365. vol. 67, No. 3-4.|
|59||Park, J.H. et al. "Hydrogels based on Poly(ethylene oxide) and poly (tetramethylene oxide) or poly)dimethyl siloxane). III. In vivo Biocompatability and Biostability." J. Biomed. Mater. Res. 64A, 2003, pp. 309-319.|
|60||Peppas et al. "Reinforced Uncrosslinkable Poly (vinyl alcohol) gels produced by cyclic freezing-thawing processes: A Short Review." J. Controlled Release, 16 (1991), 305-310.|
|61||Peppas et al. Structure and Applications of Poly(vinyl alcohol) Hydrogels Produced by Conventional Crosslinking or b Freezing/Thawing Methods. Adv. Polymer Sci. 153, 37 (2000).|
|62||Peppas et al., Physicochemical Foundations and Structural Design of Hydrogels in Medicine and Biology; Annu. Rev. Biomed Eng, vol. 2, 9-29 (2000).|
|63||Preliminary report on Patentability & Written Opinion for PCT/US2006/006356 dated Aug. 28, 2007.|
|64||Preliminary Report on Patentability & Written Opinion for PCT/US2008/071539 dated Mar. 2, 2010.|
|65||Preliminary Report on Patentability & Written Opinion for PCT/US2008/086817 dated Jul. 6, 2010.|
|66||Rao et al. J. Chem. Soc. Dalton Trans., 1939-1944.|
|67||Rosiak, J. M. & Ulanski, P. Synthesis of hydrogels by irradiation of polymers in aqueous solution, Radiation Physics and Chemistry 1999 55: 139-151.|
|68||Schmedlen, R.H. et al. "Photocrosslinkable polyvinyl alcohol hydrogels that can be modified with cell adhesion peptides for use in tissue engineering." Biomaterials, 23, 2002, pp. 4325-4332.|
|69||Search Report and Written Opinion for PCT/US2008/071435 dated Feb. 5, 2009.|
|70||Search Report and Written Opinion for PCT/US2008/083213 dated May 8, 2009.|
|71||Search Report for PCT/US2008/071435 dated Feb. 2, 2009.|
|72||Stammen, J. A., et al. Mechanical properties of a novel PVA hydrogel in shear and unconfined compression Biomaterials, 2001 22: p. 799-806.|
|73||Suggs, L.J. et al. "In vitro Cytotoxicity and in Vivo Biocompatability of Poly(propylene fumurate-co-ethylene glycol) hydrogels." J. Biomed. Mater. Res., 1999, pp. 22-32, vol. 46.|
|74||T. Noguchi et al., Poly(vinyl Alcohol) Hydrogel as an Artificial Articular Cartilage: Evaluation of Biocompatibility; Journal of Applied Biomaterials, vol. 2, 101-107 (1991), John Wesley & Sons, Inc. .|
|75||Taguchi. Chemistry Letters, 711-712 (1998).|
|76||Thomas, J.D. "Novel Associated PVA/PVDP Hydrogels for Nucleuc Pulposus Replacement." Thesis, Master of Science in Material Engineering Degree, Drexel University, Sep. 2001.|
|77||Tripathy et al. "Novel Flocculating Agent Based on Sodium Alginate and Acrylamide." European Polymer Journal. 35, 2057-2072 (1999).|
|78||Ulanski, P. et al. "OH-Radical induced crosslinking and strand breakage of poly (vinyl alcohol) in aqueous solution in the absence and presence of oxygen. A pulse radiolysis and product study" Macromol. Chem. Phys. 195, p. 1443-14461 (1994).|
|79||Urushizaki, F. Swelling and Mechanical Properties of Poly (vinyl alcohol) Hydrogels. Intl. J. Pharma., 58, 135-142, 1990.|
|80||Ushio, K. et al "Attachment of Artificial Cartilage to Underlying Bone." J. Biomed. Mater. Res. Part B: Appl. Biomater, 2004, pp. 59-68.|
|81||Ushio, K. et al. "Partial Hemiarthroplasty for the treatment of Osteonecrosis of the Femoral Head: An Experimental Study in the Dog." J. Bone Joint Surg., 2003, pp. 922-930, vol. 85B.|
|82||Wang B., et al. The Influence of Polymer concentration on the Radiation-chemical Yield of Intermolecular Crosslinking of Poly(Vinyl Alcohol) by gamma-rays in Deoxygenated Aqueous Solution. Radiation Physics and Chemistry, 2000. 59: p. 91-95.|
|83||West et al. Reactive Polymers, 139-147 (1995).|
|84||Yamaura, K., et al. Properties of gels obtained by freezing/thawing of poly(vinyl alcohol)/water/dimethyl sulfoxide solutions. Journal of Applied Polymer Science 1989 37:2709-2718.|
|85||Yamaura, Kazuo, et al, "Properties of Gels Obtained by Freezing/Thawing of Poly(vinyl Alcohol)/Water/Dimethyl Sulfoxide Solutions," Journal of Applied Polymer Science, vol. 37 pp. 2709-2718, 1989.|
|86||Yokoyama, F. "Morphology and Structure of Highly Elastic Poly (vinyl alcohol) Hydrogel Prepared by Repeated Freezing-and-Melting" Colloid & Polymer Sci. 264, 595-601 (1986).|
|87||Yokoyama, F., et al, "Morphology & Structure of highly elastic poly (vinyl alcohol) hydrogel prepared by repeated freezing-and-melting," Colloid & Polymer Science, vol. 264, pp. 595-601, 1986.|
|88||Zhang, X. et al. "Synthesis and Characterization of Partially Biodegradable, Temperature and pH Sensitive Dex-MA/PNIPAAm Hydrogels." Biomat., 25, 2004, pp. 4719-4730.|
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